Genetic studies of insulin-dependent diabetes mellitus: segregation and linkage analyses
Abstract
The inclusion of HLA data in genetic studies of insulin-dependent diabetes mellitus (IDDM) has not led to conclusive segregation models for IDDM so far. As a new approach, we first applied complex segregation analysis, independently of HLA data, to two combined Danish family materials. Then the best fitting segregation model was entered into linkage analysis of a third material, including family as well as HLA data. The best solution obtained in the segregation analysis was a mixed model, including an intermediate gene, which on the penetrance scale acts as a recessive, together with a polygenic component. The linkage analysis showed an overall recombination fraction of 0.0417 with high coupling frequencies for the HLA-DR3 and HLA-DR4 alleles and the putative disease susceptibility gene. However, when the pedigrees were divided according to whether or not the proband had the heterozygous HLA-phenotype DR3/DR4, a maximum likelihood ratio test for heterogeneity was significant, with estimated recombination fractions of 0.0 and 0.0963 in HLA-DR3/DR4 pedigrees and the remaining pedigrees, respectively. In total, we found convincing evidence that two familial factors contribute to IDDM: a locus within HLA, which very well may be DR;...Continue Reading
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